Otitis media is one of the most common causes for visits to the emergency room and the second ranking for visits to a physician's office in the United States (>20 million visits per year), costing the nation 4- 5 billion dollars annually. By three years of age, 80% of all children in the United States have had at least one episode of otitis media, and 50% have had at least three episodes. Approximately 5-10% of children with acute otitis media develop chronic otitis media with effusion. One of the histologic hallmarks with otitis media is mucous cell metaplasia/hyperplasia in the middle ear that is progressive, irreversible and destructive, which frequently leads to chronicity of otitis media and hearing loss. The pathogenesis of mucous cell metaplasia/hyperplasia in the middle ear mucosa is poorly understood. As a consequence, there is no effective treatment and prevention for mucous cell metaplasia/hyperplasia. We, therefore, propose to study the molecular mechanism by which common middle ear pathogens, such as Streptococcus pneumoniae, trigger mucous cell metaplasia/hyperplasia in the middle ear mucosa, using cellular and molecular biologic techniques. First, we will identify the receptor and signal molecules that mediate mucous cell metaplasia/hyperplasia using animal models. Second, we will determine the transcription factors that control the development of mucous cells. Third, we will use mutant mice to confirm the importance of the receptor, signal molecules, and transcription factors in mucous cell metaplasia/hyperplasia in the middle ear. Fourth, we will look for specific inhibitors (biochemical, immunological, and pharmaceutical agents) to block or inhibit the mucous cell metaplasia/hyperplasia in animal models. These studies will not only improve our understanding of otitis media but also provide innovative therapeutic strategies for prevention and treatment of otitis media in the future.